Abstract 3352: Profiling impact of genomic alterations on the BCL2-family protein interactions in acute myeloid leukemia using the SPID platform

Abstract Introduction: Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy, leading to varied therapeutic outcomes with targeted therapies. Venetoclax, a BCL2 inhibitor, has shown efficacy in treating AML patients by disrupting BCL2 functions. Genomic mutations like TP53, IDH1/2, PTPN11, and NRAS are associated with response rates to venetoclax. However, profiling the association between these mutations and BCL2-family protein interactions remains limited in clinical specimens. This study utilized the single-molecule protein interaction detection (SPID) platform to map BCL2-family interactions and examine their links to TP53, IDH1/2, PTPN11, FLT3, and NRAS mutations. Methods: Bone marrow mononuclear cells (BMMCs) from AML patients were retrospectively analyzed using the SPID platform to measure BCL2-family protein expression and complex levels. 10 assays evaluated Active BAX, Active BAK, BCL2, BIM levels, and complexes like BCL2-BAX and BCLxl-BAK. A BIM-BH3 mimicking probe quantified unoccupied anti-apoptotic protein levels. Mutational status was determined using next-generation sequencing, and Mann-Whitney U tests compared protein profiles between wildtype and mutant groups. Results: Among 80 patients (median age: 65 years), 43 (48.75%) had TP53, IDH1/2, PTPN11, FLT3, or NRAS mutations. IDH1/2 mutations were linked to higher BCL2-BAX complexes and unoccupied BCL2 levels (p<0.05). TP53 mutations were associated with reduced Active BAX and BCL2-BAX complex levels (p=0.015 and p=0.003). NRAS mutations led to reduce BCLxl-BAK (p=0.0019) and MCL1-BAK (p=0.0504) complexes, while PTPN11 mutations lowered BIM-el and MCL1-BAK levels (p<0.05). No significant biomarkers were linked to FLT3 mutations. Conclusion: This study reveals how genomic alterations in AML impact BCL2-family signaling, influencing venetoclax response. IDH1/2 mutations enhance BCL2-BAX complexes, potentially associating with favorable venetoclax sensitivity. Conversely, TP53 mutations reduce pro-apoptotic signaling, conferring resistance to venetoclax. NRAS and PTPN11 mutations affect anti-apoptotic complexes, further influencing therapeutic outcomes. Taken together, these discoveries provide how genomic alterations can impact on the BCL2-family signaling. Citation Format: Saem Hong, Yunseo Lee, Byungsan Choi, Hee-Je Kim, Byung-Sik Cho, Hongwon Lee. Profiling impact of genomic alterations on the BCL2-family protein interactions in acute myeloid leukemia using the SPID platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3352.